This competing renewal continues to utilize human knee joints from donors across the adult age spectrum to establish phenotypic changes in articular cartilage and chondrocytes that are characteristic of normal joint aging and may predispose to the development of osteoarthritis (OA). The overall goal of this program is to begin with phenotype identification, proceed to elucidation of mechanisms and key cellular and molecular abnormalities in order to provide new directions for correcting aging-associated risk factors for OA and therapeutic interventions for established OA. Access to human tissues provides a unique opportunity to test the human and clinical relevance of novel basic and molecular mechanisms not only through correlative studies but also through an array of comprehensive in vitro studies with cells isolated from human tissues. The overall hypothesis proposes that cartilage aging is associated with loss and dysfunction that differentially affects cartilage cell subpopulations. Chondrocytes are compromised in function by aging-associated changes in signaling mechanisms and the inflammatory milieu of OA. The proposed program will continue the existing cores (A: Administration;B and C now combined into Core B: Tissue Acquisition, Morphology, and Cell Culture). The following 3 projects are proposed: Project 1, "Chondrocyte subpopulations in aging and osteoarthritis" (PI: M. Lotz) will characterize chondrocyte subpopulations and the role of Sox9-dependent activation of chondrocytes in normal and aging cartilage. Project 2, "Dysfunctional chondrocyte differentiation in aging cartilage" (PI: R. Terkeltaub) addresses the regulation of articular chondrocyte hypertrophy by altered Pi and PPi metabolism with focus on specific enzymes (NPP1, TNAP) and transporters (Ank, Pit-1). Project 4, "Mechanobiology of human articular cartilage degeneration: aging and osteoarthritis" (PI: R. Sah) will analyze biomechanical mechanisms of early and advanced cartilage degeneration and determine consequences for chondrocyte function and survival. Collectively, the results from the proposed studies will add important new information on chondrocyte biology, cartilage aging, and osteoarthritis pathophysiology. RELEVANCE: Joint aging is the major risk factor for the osteoarthritis, the most prevalent joint disease. Therapies that modify the progressive cartilage destruction process are not available. This program represents a comprehensive analysis of cellular end extracellular matrix changes that are associated with aging and osteoarthritis. Defining mechanisms of healthy joint aging and pathogenetic mechanisms of osteoarthritis has the potential to lead to new osteoarthritis markers and therapies. PRINCIPAL INVESTIGATOR: Dr. Martin Lotz holds the appointments of Professor in the Department of Molecular and Experimental Medicine and Head of the Division of Arthritis Research at the Scripps Research Institute. He also has a faculty appointment at the University of California, San Diego, the other institution involved in the program. He has been a part of this program since its inception in 1988 and has served as Principal Investigator (PI) since 1996. Dr. Lotz is an established investigator in the fields of cartilage biology and osteoarthritis pathogenesis and is internationally recognized for his research. His participation and leadership constitute a major strength of this program project. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A - ADMINISTRATION;Dr. Martin K. Lotz, Core Leader DESCRIPTION (provided by applicant): The central theme of the Program is to study aging of human articular cartilage and chondrocytes and its relationship to osteoarthritis. The Administrative Core will focus efforts of the cores and projects on this topic, advance hypotheses and research directions, and ascertain scientific progress. The Specific Aims of the Administrative Core are: 1. Monitor scientific progress in the individual projects. The core is responsible for stimulating and focusing discussions among the participants of the Program on aging of human cartilage. Regular monthly seminars will be held where each project presents a progress report. At annual meetings with the Scientific Advisory Committee, progress is evaluated and efforts are redirected. 2. Promote interactions among the investigators in the Program. Wherever possible, potential interactions will be identified and brought to successful realization. Specific themes for interactions have been defined and productivity in terms of co-authored publications will be reviewed annually. 3. Support young scientists and development of new projects. Young scientists are included as coinvestigators in this program. They are supported through mentoring, access to human tissues and assistance in preliminary data generation and statistical analysis for grant applications. 4. Provide access to cartilage samples. 5. Establish and maintain central database. The Administrative Core has established and will maintain a database with information on all cartilage samples that are studied in the Program. Research data from the Projects will be entered into the central database for analysis. Statistical analysis. We will perform data analysis for Core B and the individual projects and establish correlations between measurements obtained in the 3 projects. 7. Coordinate all fiscal activities of the Program. 8. Ascertain responsible conduct of research. This Program is using human tissue and animals. The Administrative Core surveys that all activities involving human tissue and animals are performed in accordance with HIPPA, NIH, and IACUC guidelines. 9. Enforce safety measures for work with hazardous materials. RELEVANCE: The central theme of the Program is to study aging of human articular cartilage and chondrocytes and its relationship to osteoarthritis. The Administrative Core will focus efforts of the cores and projects on this topic, advance hypotheses and research directions, and ascertain scientific progress.